The overall objective of this research career award application is to understand the role of the default pathway of apoptosis in the pathogenesis of acute renal failure (ARF). The goal of this application is to provide additional training in the rodent acute renal failure model and molecular biology technology to facilitate the candidates transition to an independent scientist in the field of apoptotis research relating to kidney disease. Previous studies on the role of apoptosis in ARF have focused on cytotoxic stimuli as inducers of apoptosis. We suggest that apoptosis of renal tubular cells is due not only to direct cellular injury but also to a relative deficiency of survival factors. Moreover, we suggest that the therapeutic efficacy of growth factors in experimental ARF is mediated, in part, through suppression of cell death and the default pathway of apoptosis. We aim to approach these questions in two ways. An in vitro approach will elucidate the signaling pathways and/or intracellular mediators by which spontaneous activation of ERK1/2 in Mouse Kidney Proximal Tubule (MKPT) cells deprived of all soluble survival factors induces down-regulation of Akt and promotes MKPT cell apoptosis. Through the use of cell signaling and molcular biology tools, we will dissect the mechanism of this relationship and with the use of gene array and transcription factor analysis we will map the downstream events occurring during the default pathway of apoptosis. The in vivo approach will examine the role of the ERK1/2 pathway in recovery from experimental ischemic ARF agin using molcular approaches. Interventions that ameliorate apoptosis during the recovery phase of ARF have great therapeutic potential, since they can be administered after the onset of ARF without the need to anticipate when ARF will occur. The candidate, Vimal Patel, is an Instructor at the University of Illinois, Chicago and the training team of Jerrold Levine, David Ucker, Jose Arruda, David Basile, Wil Leiberthal, Mike Abecassis and John Schwartz consists of established experts in the apoptosis and acute renal failure fields. There is institutional commitment and a integrated career development plan encompasing a broad range of activities. Taken together these studies will improve our understanding of the default pathway in ARF and provide Dr. Patel the rigorous training needed to facilitate his goal of an independent research career. Moreover, these studies should also help in understanding the default pathway of apoptosis in other cell and organ systems.